Platelets exacerbate cardiovascular inflammation in a murine model of Kawasaki disease vasculitis
Begüm Kocatürk, Youngho Lee, Nobuyuki Nosaka, Masanori Abe, Daisy Martinon, Malcolm E. Lane, Debbie Moreira, Shuang Chen, Michael C. Fishbein, Rebecca A. Porritt, Bernardo S. Franklin, Magali Noval Rivas, Moshe Arditi
Begüm Kocatürk, Youngho Lee, Nobuyuki Nosaka, Masanori Abe, Daisy Martinon, Malcolm E. Lane, Debbie Moreira, Shuang Chen, Michael C. Fishbein, Rebecca A. Porritt, Bernardo S. Franklin, Magali Noval Rivas, Moshe Arditi
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Research Article Inflammation Vascular biology

Platelets exacerbate cardiovascular inflammation in a murine model of Kawasaki disease vasculitis

Abstract

Kawasaki disease (KD) is the leading cause of acquired heart disease among children. Increased platelet counts and activation are observed during the course of KD, and elevated platelet counts are associated with higher risks of developing intravenous immunoglobulin resistance and coronary artery aneurysms. However, the role of platelets in KD pathogenesis remains unclear. Here, we analyzed transcriptomics data generated from the whole blood of patients with KD and discovered changes in the expression of platelet-related genes during acute KD. In the Lactobacillus casei cell wall extract (LCWE) murine model of KD vasculitis, LCWE injection increased platelet counts and the formation of monocyte-platelet aggregates (MPAs), upregulated the concentration of soluble P-selectin, and increased circulating thrombopoietin and interleukin 6 (IL-6). Furthermore, platelet counts correlated with the severity of cardiovascular inflammation. Genetic depletion of platelets (Mpl–/– mice) or treatment with an anti-CD42b antibody significantly reduced LCWE-induced cardiovascular lesions. Furthermore, in the mouse model, platelets promoted vascular inflammation via the formation of MPAs, which likely amplified IL-1B production. Altogether, our results indicate that platelet activation exacerbates the development of cardiovascular lesions in a murine model of KD vasculitis. These findings enhance our understanding of KD vasculitis pathogenesis and highlight MPAs, which are known to enhance IL-1B production, as a potential therapeutic target for this disorder.

Authors

Begüm Kocatürk, Youngho Lee, Nobuyuki Nosaka, Masanori Abe, Daisy Martinon, Malcolm E. Lane, Debbie Moreira, Shuang Chen, Michael C. Fishbein, Rebecca A. Porritt, Bernardo S. Franklin, Magali Noval Rivas, Moshe Arditi

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Figure 4

Decreased development of LCWE-induced cardiovascular lesions in thrombocytopenic Mpl–/– mice.

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Decreased development of LCWE-induced cardiovascular lesions in thromboc...
(A and B) Representative H&E-stained heart tissue sections (A) and heart inflammation score (B) of LCWE-injected WT and Mpl–/– mice 1 week after LCWE injection (n = 12/group). Scale bars: 200 μm. (C and D) Representative pictures of the abdominal aorta area (C) and maximal abdominal aorta diameter and abdominal aorta area measurements (D) from WT and Mpl–/– mice (n = 15–17/group) at 1 week after LCWE injection. (E) Heatmap illustrating the expression of S100a8 and S100a9 (at least 1.5 FC with an adjusted P value < 0.05) in abdominal aorta tissues of PBS- and LCWE-injected mice (n = 5/groups; GSE141072). Blue–red color gradient: Low to high expression relative to the mean of each column. Each row represents 1 mouse of the defined groups. (F) Calprotectin levels in the serum of PBS- and LCWE-injected WT and Mpl–/– mice, at 1 week after injection (n = 4 to 12/group). Each symbol represents 1 mouse. Results presented as mean ± SEM pooled from 2–3 independent experiments. *P < 0.05; ****P < 0.0001 obtained by unpaired 2-tailed Student’s t test with Welch’s correction (B), unpaired 2-tailed Student’s t test (D), or 2-way ANOVA with Tukey’s multiple-comparison test (F).